Chen J, Xu L, Liu TY
… +9 more, Chen WJ, Dai B, Rong SK, Lan ZT, Wang LH, Liu YC, Li JH, Li L, Wu ZY
Endocrinology
· 2026 Feb · PMID 41631714
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Follicular thyroid carcinoma (FTC) is prone to early distant metastasis and has a poor prognosis compared with papillary thyroid carcinoma (PTC). This study aimed to unravel the cellular and molecular mechanisms underlyi...Follicular thyroid carcinoma (FTC) is prone to early distant metastasis and has a poor prognosis compared with papillary thyroid carcinoma (PTC). This study aimed to unravel the cellular and molecular mechanisms underlying FTC progression and its transformation into the aggressive anaplastic thyroid carcinoma (ATC). Through single-cell RNA sequencing (scRNA-seq) profiling of 46 739 cells from PTC, follicular variant PTC (FVPTC), relapsed FTC (RFTC), and ATC, we reconstructed a comprehensive molecular trajectory of thyroid carcinoma progression. Our analysis revealed that PTC, FVPTC, and FTC possess distinct yet converging pathways of dedifferentiating into ATC, with FVPTC also able to progress to FTC. In RFTC, we identified a unique cluster of cells exhibiting ATC molecular characteristics. These cells interact with endothelial cells and fibroblasts mainly via the COL9A3-integrin α1β1 complex and may exhibit high metabolic and proliferative potential. UBE2C was identified as a specific marker for this population, which we termed "ATC-like cells." Functional validation in vitro and in vivo confirmed that UBE2C was markedly upregulated in FTC and was associated with adverse clinical outcomes. Mechanistically, UBE2C promoted cell proliferation and tumor growth, and regulated D-arginine and D-ornithine metabolism, glutathione metabolism, glycerophospholipid metabolism and tryptophan metabolism in FTC. This reveals a previously unrecognized population of ATC-like cells in RFTC marked by high UBE2C expression. UBE2C contributes to FTC progression by enhancing proliferation and modulating key metabolic pathways, suggesting it as both a critical biomarker of aggressive disease and a potential therapeutic target.
Gafiyatullina G, Shabalova A, Goto H
… +18 more, Oo HK, Saito K, Tanida R, Li Q, Kamoshita K, Galicia-Medina CM, Nakano Y, Takeshita Y, Ishii KA, Takayama H, Tsuji C, Higashida H, Shinmyo Y, Kawasaki H, Tsujiguchi H, Hara A, Nakamura H, Takamura T
Endocrinology
· 2026 Jan · PMID 41612851
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CONTEXT: Diabetes-associated metabolic stress and anxiety reciprocally influence one another's onset and course. We previously linked excessive selenoprotein P (SeP, encoded by SELENOP in humans) to pathological conditio...CONTEXT: Diabetes-associated metabolic stress and anxiety reciprocally influence one another's onset and course. We previously linked excessive selenoprotein P (SeP, encoded by SELENOP in humans) to pathological conditions frequently observed in individuals with diabetes. OBJECTIVE: The present study aimed to clarify the role of SeP in the metabolic stress-induced anxiety. METHODS: We visualized Selenop expression in the mouse brain section via RNAscope in situ hybridization and used RT-qPCR to evaluate gene expression in brain regions. We created brain-specific Selenop knockout (bSelenop-/-) mice by mating Selenop-flox and Nestin-Cre mice and conducted behavior tests for anxiety-like behavior and spatial memory under both a standard (STD) and high-fat, high-sucrose diet (HFHSD) conditions. In a cross-sectional general population cohort study, we examined differences in serum selenoprotein P concentrations between individuals with and without anxiety symptoms. RESULTS: RNAscope in situ hybridization identified glial and endothelial cells as the sources of SeP synthesis in the brain. Selenop was expressed at the same level in the brains of mice fed with an STD and HFHSD. bSelenop-/- mice did not exhibit altered body weight or glucose tolerance associated with HFHSD feeding. High-fat, high-sucrose diet aggravated the anxiety-like behavior in the control mice, whereas Selenop deletion in the brain ameliorated the anxiety-like behavior without affecting spatial memory. Epidemiological data revealed that serum selenoprotein P was significantly higher in subjects with anxiety symptoms. CONCLUSION/INTERPRETATION: These findings suggest that excess SeP production may be a common trait linking metabolic stress with anxiety.
Golden TN, Garifallou JP, Conine CC
… +1 more, Simmons RA
Endocrinology
· 2026 Jan · PMID 41604432
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Immune cells in the pancreas are known to participate in organ development. However, the resident pancreatic immune system has yet to be fully defined. Immune cells also play a role in pathology and are implicated in dis...Immune cells in the pancreas are known to participate in organ development. However, the resident pancreatic immune system has yet to be fully defined. Immune cells also play a role in pathology and are implicated in diseases such as diabetes induced by intrauterine growth restriction (IUGR). We hypothesized that the resident immune system continues to develop during the neonatal period and is disrupted by IUGR. Using single-cell RNAseq and flow cytometry we identified many immune cell populations in the near-term fetus (at embryologic day 22) and neonatal (postnatal day 1, 7, &14) islets, non-endocrine pancreas, and the spleen in the rat. Using flow cytometry, we observed that the resident immune system dynamically changes during neonatal development in the pancreas and spleen. We identified 14 distinct immune populations in the pancreatic islets and 13 distinct immune populations in the spleen by single-cell RNAseq. There were no sex-specific differences in the relative proportion of immune cells in the pancreas or spleen. Finally, we tested if IUGR disrupted the neonatal immune system using bilateral uterine artery ligation. We found significant changes to the percentage of CD11B+ HIS48- and B cells in the islets and non-endocrine pancreas. IUGR-induced alterations were influenced by the tissue environment. Future research to define the role of these immune cells in pancreatic development may identify disrupted pathways that contribute to the development of diabetes following IUGR.
Barrile F, Cornejo MP, De Francesco PN
… +6 more, de Souza GO, Dos Santos WO, Wasinski F, Kopchick JJ, Donato J, Perelló M
Endocrinology
· 2026 Jan · PMID 41554688
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Ghrelin acts via the growth hormone secretagogue receptor (GHSR) and increases both food intake and growth hormone (GH) secretion. Studies in mice with genetic manipulations of GH receptor (GHR) revealed that GH action i...Ghrelin acts via the growth hormone secretagogue receptor (GHSR) and increases both food intake and growth hormone (GH) secretion. Studies in mice with genetic manipulations of GH receptor (GHR) revealed that GH action is required for ghrelin's orexigenic effects. However, the biological basis of this interdependence remains unclear. Here, we studied the mechanisms by which GHR contributes to ghrelin-induced hyperphagia in male mice. Transcriptomic analyses of single-cell datasets revealed that Ghr and Ghsr are co-expressed in a small subset of neurons, particularly within the hypothalamic arcuate nucleus (ARH). Systemic ghrelin administration increased food intake, circulating GH, and glycemia but did not induce GHR activation in the brain, as indicated by the absence of pSTAT5 immunoreactivity. Central GH administration failed to enhance ghrelin-induced food intake or glycemia. To evaluate the role of peripheral GHR signaling, we treated mice with the brain-impermeable GHR antagonist pegvisomant. Systemically injected pegvisomant impaired ghrelin's orexigenic effect without affecting its impact on glycemia or hypothalamic c-Fos activation, indicating that peripheral GHR signaling is required for ghrelin-induced hyperphagia. Pegvisomant did not alter refeeding-induced or AgRP neuron-mediated hyperphagia, suggesting a selective blockade of ghrelin's action. Moreover, ghrelin-induced food intake was preserved in hepatocyte-specific GHR knockout mice, despite disrupted hepatic GH signaling. Thus, peripheral, non-hepatic GHR signaling is selectively required for the orexigenic effects of ghrelin. This work reveals a critical GH-dependent, liver-independent mechanism underlying ghrelin-driven feeding, with potential implications for the neuroendocrine regulation of appetite and for therapeutic strategies targeting the ghrelin-GH axis in metabolic diseases.
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the destruction of insulin-producing β-cells in the pancreatic islets, resulting in complete insulin deficiency. The pathogenesis of T1D is multifact...Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the destruction of insulin-producing β-cells in the pancreatic islets, resulting in complete insulin deficiency. The pathogenesis of T1D is multifactorial and includes genetic predisposition and environmental triggers. Recent research has highlighted the role of microRNAs (miRNAs) in regulating immune responses and β-cell function, making them promising biomarkers and therapeutic targets. Our research included published articles focused on MiRNAs are small, non-coding RNA molecules that modulate gene expression post-transcriptionally, influencing processes such as cell proliferation, differentiation and apoptosis. Data was gathered from different sources including different databases. This review examines the biogenesis and function of miRNAs, their involvement in T1D pathogenesis, and their potential role as therapeutic targets. Also addressing the challenges and future directions for miRNA-based therapies. In T1D, miRNAs have been shown to regulate immune-mediated β-cell destruction and inflammatory responses, contributing to disease progression. miR-21, miR-146a, and miR-155 play important roles in modulating immune pathways that influence β-cell survival. Due to their potential for early diagnosis and therapeutic modulation, miRNAs are being explored as non-invasive biomarkers detectable in blood and urine and targets for therapeutic interventions. However, challenges related to the specificity of the miRNA targeting, stability, and delivery systems must be addressed to realize their clinical potential. Nanoparticle-based delivery systems promise to overcome these challenges by increasing the precision of miRNA targeting and improving their stability.
BACKGROUND: Prenatal exposure to dioxin, a known endocrine disruptor, after the Seveso accident of 1976 has been associated with thyroid dysfunction, metabolic syndrome and semen quality reduction. Experimental exposure...BACKGROUND: Prenatal exposure to dioxin, a known endocrine disruptor, after the Seveso accident of 1976 has been associated with thyroid dysfunction, metabolic syndrome and semen quality reduction. Experimental exposure to dioxin in utero produced epigenetic endocrine modifications associated with reduction of semen quality, while in men epigenetic effects are not known. Our objective was to study, by a case control approach, the long-term epigenetic effects of prenatal dioxin exposure in 38 men whose mothers had been exposed to high doses of dioxin, serum median 52.0 ppt at exposure, and therefore who were exposed in utero, median 24.7 ppt at pregnancy, vs. 41 unexposed men. METHODS: Bisulfite-converted DNA was hybridized onto illumina Infinium Methylation EPIC BeadChip and methylation differences were studied at both individual probe (DMPs) and gene region (DMRs) levels. RESULTS: We identified hypomethylation of the SPAG1 gene region and a slightly hypermethylated region containing genes of the HOXA family associated with thyroid and skeletal development. An elevated level of epigenetic drift was noted in the exposed group potentially contributing to disease risk. Epigenetic age acceleration did not show significant association with in-utero dioxin exposure. Additionally, we found heightened neutrophils and diminished natural killer cells in blood of dioxin exposed men. CONCLUSIONS: These observations are the first in the literature and align with the long-term semen quality reduction and alteration of thyroid homeostasic mechanisms reported in children exposed in utero to dioxin in Seveso. The actual dioxin background serum levels, 1.0-2.0 ppt, are much lower than those associated to these effects.
Walsh C, Scott E, Wagner E
… +9 more, Walsh J, Reddy S, Ahmad A, Basu R, Sevick-Muraca E, Brody R, Sandbhor U, Neggers S, Kopchick JJ
Endocrinology
· 2026 Jan · PMID 41549747
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Disruption of lymphatic function underlies a broad spectrum of inflammatory and metabolic disorders, yet the hormonal pathways that regulate lymphatic biology remain poorly defined. GH, which is implicated in similar dis...Disruption of lymphatic function underlies a broad spectrum of inflammatory and metabolic disorders, yet the hormonal pathways that regulate lymphatic biology remain poorly defined. GH, which is implicated in similar disease states, has an unclear role in lymphatic homeostasis. To address this gap, we investigated how chronic alterations in GH signaling alter lymphatic structure and function. Using transgenic mouse lines with increased, decreased, or absent GH action, we quantified the effect of GH on lymphatic pumping rate and lymphangiogenic remodeling during wound healing using near-infrared fluorescent imaging. We also measured markers of lymphatic endothelial cells using Western blot and immunohistochemistry across multiple mouse organs. Lymphatic pumping rate positively correlated with GH action, whereas both elevated and absent GH signaling delayed wound healing. In contrast, the lymphatic vascular density and the expression of protein markers of lymphatic endothelial cells were inversely correlated with GH activity. Additionally, we showed that primary human dermal lymphatic endothelial cells express the GH receptor and exhibit acute GH-activated signaling and that this activation can be blocked with new and Food and Drug Administration-approved GH receptor antagonists. Together, these findings identify GH as a regulator of the lymphatic system and suggest that GH receptor antagonism could be a potential strategy to address lymphatic dysfunction.
Obesity is a risk factor for chronic diseases and early death; however, the underlying mechanisms are not fully understood. Whereas insulin resistance and inflammation are established pathways in several of these relatio...Obesity is a risk factor for chronic diseases and early death; however, the underlying mechanisms are not fully understood. Whereas insulin resistance and inflammation are established pathways in several of these relationships, it is less clear how increases in body adipose tissue relate to these pathways and disease risk. Several adipose tissue-derived blood-based biomarkers have been identified as purported mediators, including adipokines, inflammatory cytokines and sex steroid hormones. Traditionally, these markers were discovered in animal models and their relevance in humans has then been investigated in epidemiological studies. Today, proteomics and metabolomics approaches in human observational studies are used to discover obesity biomarkers in blood, supported by Mendelian randomization studies to draw causal inferences. Here we review adipose tissue-derived blood-based obesity biomarkers and their relevance for disease risk, along with their potential role as mediators. Proteomics and metabolomics studies have partly re-identified traditional biomarkers, but more large-scale prospective analyses are needed to obtain evidence of the relevance of omics-based and traditional obesity biomarkers to disease.
Endocrinology
· 2026 Jan · PMID 41537577
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Progesterone receptor membrane components 1 and 2 (PGRMC1 and PGRMC2) are single-pass proteins that function as multi-ligand regulators. They integrate signals from progesterone (P4), heme, and cytochrome P450 enzymes (C...Progesterone receptor membrane components 1 and 2 (PGRMC1 and PGRMC2) are single-pass proteins that function as multi-ligand regulators. They integrate signals from progesterone (P4), heme, and cytochrome P450 enzymes (CYPs). Accumulating evidence implicates PGRMCs in non-genomic progesterone signaling in cell, cancer, and reproductive biology. Heme binding (through their heme binding domain) and cytochrome P450 enzymes (CYPs) binding provide distinct functional roles for PGRMCs in various cells under specific cellular environment. In reproductive tissues, multiple functional roles have been reported for both PGRMC1 and PGRMC2 in both maternal and fetal organs. Ambiguity still exists about their independent functional role and contributions in pregnancy maintenance or initiation of parturition. Collectively, PGRMC1 and PGRMC2 act in complementary ways to regulate heme biology, metabolism, and P4-responsive signaling in gestational tissues. With the growing interest in PGRMC's role in pregnancy associated tissues, we provide a comprehensive narrative of PGRMCs through this review to facilitate future research and stimulate continued discussions.
Nishinoiri A, Tokumaru K, Kanazawa G
… +10 more, Shintani Y, Yoshitake T, Yamamoto T, Fukuta S, Nishimura A, Nishida M, Takeo T, Maeda H, Maruyama T, Watanabe H
Endocrinology
· 2026 Jan · PMID 41537567
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Dysregulation of hepatokines has been observed in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), suggesting their involvement in disease progression. In this study, we aimed to investigat...Dysregulation of hepatokines has been observed in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), suggesting their involvement in disease progression. In this study, we aimed to investigate the role of α1-acid glycoprotein (AGP), a hepatokine, in the progression of MASLD and to evaluate its potential therapeutic utility. Reanalysis of hepatic RNA sequencing datasets from patients with fatty liver disease showed that expression of the hepatic AGP gene decreased with disease progression. A high-fat diet (HFD)-induced mouse model of MASLD also showed decreased plasma and hepatic AGP levels. Whole-body AGP-knockout (AGP-KO) mice were fed a HFD for 12 weeks. Compared to wild-type mice, AGP-KO mice fed a HFD displayed further exacerbated hepatic steatosis, obesity, adipose tissue inflammation, and impaired glucose tolerance, suggesting a protective role for endogenous AGP against MASLD. Morphological abnormalities of hepatic mitochondria were observed in AGP-KO mice. Human-derived AGP (hAGP) was isolated and purified from plasma fraction V supernatant derived from human blood donations using ion-exchange column chromatography. hAGP exerted a protective effect against palmitate-induced lipotoxicity in hepatocytes, adipocytes, and macrophages. Exogenous administration of hAGP to MASLD mice attenuated disease progression by reducing hepatic mitochondrial dysfunction and adipose tissue inflammation. In conclusion, decreased endogenous AGP levels may contribute to the disease progression of MASLD. AGP has the potential to serve as a novel therapeutic agent against MASLD by targeting both liver and adipose tissue.
Endocrinology
· 2026 Feb · PMID 41527917
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Type 2 diabetes (T2D) is a heterogenous metabolic condition characterized by varying degrees of insulin resistance and β-cell dysfunction. Preclinical mouse models are essential tools to investigate the mechanisms of T2D...Type 2 diabetes (T2D) is a heterogenous metabolic condition characterized by varying degrees of insulin resistance and β-cell dysfunction. Preclinical mouse models are essential tools to investigate the mechanisms of T2D pathogenesis and develop therapeutic targets; yet, researchers often fail to specify which aspects of the spectrum of human T2D phenotypes are being modeled. In this mini-review, we critically examine mouse models of T2D and categorize them into recently redefined T2D subtypes according to key pathophysiological features. We focus on models that exhibit (1) insulin deficiency, (2) insulin resistance independent of weight gain, or (3) insulin resistance associated with weight gain. Onset, severity, and progression of metabolic phenotypes are described and discussed in context with clinical presentation in humans. While we find current T2D mouse models do not fully capture the heterogeneity of T2D, strategic model combinations and longer-term phenotyping could help better mimic clinical progression. Existing phenotyping data are often incomplete and largely available only for young male mice. We highlight the urgent need for thorough and standardized phenotyping of both sexes in all models. We also encourage the field to move toward using age-appropriate mice to better reflect human T2D pathophysiology and to advance precision medicine efforts in diabetes research.
Armani A, Gorini S, Feraco A
… +3 more, Mammi C, Bellucci E, Caprio M
Endocrinology
· 2026 Mar · PMID 41521767
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The mineralocorticoid receptor (MR), classically known for its role in electrolyte homeostasis, has emerged since the early 2000s as a key regulator of adipocyte biology. MR activation induces oxidative stress and inflam...The mineralocorticoid receptor (MR), classically known for its role in electrolyte homeostasis, has emerged since the early 2000s as a key regulator of adipocyte biology. MR activation induces oxidative stress and inflammation, promotes white adipogenesis, and suppresses brown fat differentiation, potentially contributing to obesity and metabolic syndrome (MetS). In mice, MR antagonists (MRAs) have shown beneficial metabolic effects by reversing adipose tissue dysfunctions, counteracting excessive expansion of fat depots, and enhancing brown adipose tissue (BAT) thermogenesis. Clinical translation remains limited, with inconsistent outcomes in individuals with overweight or obesity, and concerns about side effects of steroidal MRAs (sMRAs), particularly hyperkalemia. Nevertheless, recent data showed that MRAs are able to activate BAT in healthy individuals and in patients with familial partial lipodystrophy type 2 (FPLD2). Nonsteroidal MR antagonists (nsMRAs), such as finerenone, exhibit anti-inflammatory and antifibrotic properties in the kidney and heart, with improved safety profiles compared to sMRAs, and are currently being explored in metabolic disorders beyond cardiorenal disease. This review summarizes novel insights into MR function in adipose tissue and critically evaluates whether MR can still be considered a valid target to treat obesity and associated metabolic disorders.
Ramsay SD, Kilgariff DE, Young BJ
… +11 more, Darveniza LC, O'Hare Doig RL, Hollis CA, Hurtado PR, Plummer MP, Robins EG, Lee JH, Meyer EJ, Nenke MA, Torpy DJ, Young RL
Endocrinology
· 2026 Jan · PMID 41521757
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Septic shock urgently requires new treatments. We reported that low circulating concentrations of the native glucocorticoid carrier, corticosteroid-binding globulin (CBG), predict a 3-fold increase in human septic shock...Septic shock urgently requires new treatments. We reported that low circulating concentrations of the native glucocorticoid carrier, corticosteroid-binding globulin (CBG), predict a 3-fold increase in human septic shock mortality. To explore this, we used our murine model of high-grade polymicrobial sepsis (cecal ligation and puncture [CLP]) to test CBG therapy. We prefitted adult male C57BL/6 mice (n = 106) with wireless arterial telemetry, then induced high-grade CLP. Mice were randomized with or without intravenous CBG therapy at 6 hours (3.5 mg/kg) and 30 hours (2.5 mg/kg). Terminal bloods, collected on humane endpoints or at 96 hours, were assessed for inflammation and organ damage; positron emission tomography was used to assess [124I]I-CBG biodistribution. CLP mice developed septic shock leading to multi-organ failure and 58% mortality. CBG therapy reduced mortality to 17% (a relative decrease of 72%), reduced hypotension duration by 75%, and lowered organ damage markers. CBG transiently suppressed the pro-inflammatory cytokine peak at 12 hours (45%-59%) and markedly augmented anti-inflammatory interleukin-10 and interferon-β1 (2-fold to 96 hours). The decrease in corticosterone alongside this profile suggests an intrinsic anti-inflammatory response. Combined with PET-confirmed [124I]I-CBG targeting to the injury site, these data suggest CBG survival benefits are due to targeted delivery or direct immunomodulation. While host responses involve a complex interplay of neuroendocrine and metabolic factors, our findings demonstrate marked improvements in disease progression and mortality with CBG therapy in murine-modeled septic shock. These results provide a strong impetus for a study of CBG therapy in patients with septic shock.
Upon fasting, mammals undergo a fasting response in which the liver's main role is producing fuel (glucose and ketone bodies) to supply extra-hepatic tissues. Glucose is produced by glycogenolysis and gluconeogenesis, an...Upon fasting, mammals undergo a fasting response in which the liver's main role is producing fuel (glucose and ketone bodies) to supply extra-hepatic tissues. Glucose is produced by glycogenolysis and gluconeogenesis, and ketone bodies are produced by ketogenesis, which is preceded by lipolysis and fatty acid oxidation. Hepatic fuel production during fasting is controlled by hormonal and metabolic cues, collectively termed here 'fasting cues'. In this Review, we discuss fasting cues that directly signal hepatocytes and whose plasma levels increase upon fasting, namely, glucagon, glucocorticoids, growth hormone, adrenaline, free fatty acids, asprosin and GP73. We outline the fasting-dependent increases in blood levels of these cues, how they regulate transcription and the metabolic consequences of these cues in hepatocytes. We put particular emphasis on their role in directing fuel production. The perception of endocrine control of fuel production is shifting from the classic 'counter-regulatory' notion that fasting cues are simply opposing insulin action, to the realization that fasting cues cooperate with each other to elicit a synergistic response and also complement each other's actions indirectly. We discuss these modes of crosstalk and cooperation between fasting cues and describe the effects of signal integration on the transcriptional and metabolic response to fasting.
Thyroid dysfunction and diabetes mellitus frequently occur together, with evidence showing higher rates of each condition in individuals affected by the other. Beyond their statistical association, emerging research indi...Thyroid dysfunction and diabetes mellitus frequently occur together, with evidence showing higher rates of each condition in individuals affected by the other. Beyond their statistical association, emerging research indicates shared mechanisms involving autoimmunity, obesity, ageing and insulin resistance, which might explain their bidirectional relationship. This Review synthesizes current evidence on these links, with a particular focus on how thyroid dysfunction influences glycaemic control and how antidiabetic therapies affect thyroid function. Unlike earlier reviews, we frame thyroid disorders within the broader category of non-communicable diseases (NCDs), emphasizing their public health relevance and the need for greater attention in global funding and policy agendas. By combining clinical insights with a population health perspective, this Review aims to promote earlier detection, integrated management strategies and recognition of thyroid disease as a neglected NCD priority.
Gang N, Nian C, Filatov E
… +5 more, Zhang D, Hoyeck MP, Laforest B, Lynn FC, Bruin JE
Endocrinology
· 2026 Feb · PMID 41502145
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Glucose homeostasis is tightly controlled by hormones secreted from pancreatic islets. The most abundant cell type in islets is the β-cell, which secretes insulin in response to nutritional stimuli. We previously reporte...Glucose homeostasis is tightly controlled by hormones secreted from pancreatic islets. The most abundant cell type in islets is the β-cell, which secretes insulin in response to nutritional stimuli. We previously reported that the adverse metabolic effects of high-dose dioxin exposure in mice are regulated by the aryl hydrocarbon receptor (AHR) specifically in β-cells. Additionally, fetal exposure to low-dose dioxin reduced β-cell area in female mice at birth; however, the role of AHR in β-cell development has not been explored. To characterize the AHR pathway in developing human β-cells, we differentiated human embryonic stem cells (hESCs) into "islet-like" cell clusters (SC-islets) in vitro and treated cells with vehicle or dioxin for 24 hours at key stages of differentiation. Dioxin exposure robustly upregulated AHR gene targets (CYP1A1, AHRR) at all stages of differentiation but only had modest effects on markers of islet development and maturity. We next generated an AHR knockout (KO) hESC line and found that basal CYP1A1 expression was profoundly suppressed in AHR-KO cells compared to parental cells at all stages of differentiation. Key markers of developing and mature pancreatic islets were largely unaffected by AHR deletion; however, G6PC2 was consistently downregulated in SC-islets from AHR-KO cells compared to parental cells. Interestingly, AHR-KO SC-islets also showed modestly increased insulin secretion relative to the parental line, suggesting a role for AHR in islet development. This novel AHR-KO cell line will allow for deeper investigation into the impact of AHR on the development of human islets and other cell lineages.
D'Souza NC, Aleali N, Shakeri D
… +7 more, Atherley SC, Hoffman EG, Karimi Chahartash S, Javanbakhsh S, Chan O, Liggins RT, Riddell MC
Endocrinology
· 2026 Jan · PMID 41502124
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In diabetes, glucagon is typically oversecreted during hyperglycemia but undersecreted during hypoglycemia. Administration of a somatostatin receptor antagonist (SSTR2a) increases glucagon counterregulation during hypogl...In diabetes, glucagon is typically oversecreted during hyperglycemia but undersecreted during hypoglycemia. Administration of a somatostatin receptor antagonist (SSTR2a) increases glucagon counterregulation during hypoglycemia in rodent models of type 1 diabetes (T1D) but less is known about its effect on glucagon in type 2 diabetes (T2D). Using a rodent model of insulin-requiring diabetes, we evaluated the effects of daily SSTR2a administration with insulin dosing (study A: 8 days) and repeated exposures to hypoglycemia (study B: 4× over 11 days) on glucagon and glycemia. In study A, 8 days of SSTR2a treatment at 3.0 mg/kg transiently increased glucagon levels after dosing but did not significantly affect the glycemic response to basal or bolus insulin. In study B, with daily low-dose SSTR2a treatment (0.3 mg/kg/d), the glucagon counterregulatory response to insulin-induced hypoglycemia increased while time to hypoglycemic onset was delayed on challenge days 1 and 2. SSTR2a treatment did not affect food intake, body mass, or C-peptide levels, but was associated with a lower glycated hemoglobin A1c level at the end of the study relative to controls (4.3 ± 0.9 vs 5.3 ± 0.8%; P < .05). In summary, in a rat model of insulin-treated T2D, daily SSTR2a administration increased glucagon counterregulation to hypoglycemia without worsening overall insulin sensitivity or glycemic control.